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Genome profiling of sterol synthesis shows convergent evolution in parasites and guides chemotherapeutic attack

Fügi, Matthias A. and Gunasekera, Kapila and Ochsenreiter, Torsten and Guan, Xueli and Wenk, Markus R. and Mäser, Pascal. (2014) Genome profiling of sterol synthesis shows convergent evolution in parasites and guides chemotherapeutic attack. Journal of Lipid Research, 55 (5). pp. 929-938.

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Official URL: http://edoc.unibas.ch/dok/A6263151

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Abstract

Sterols are an essential class of lipids in eukaryotes, where they serve as structural components of membranes and play important roles as signaling molecules. Sterols are also of high pharmacological significance: cholesterol-lowering drugs are blockbusters in human health, and inhibitors of ergosterol biosynthesis are widely used as antifungals. Inhibitors of ergosterol synthesis are also being developed for Chagas's disease, caused by Trypanosoma cruzi. Here we develop an in silico pipeline to globally evaluate sterol metabolism and perform comparative genomics. We generate a library of hidden Markov model-based profiles for 42 sterol biosynthetic enzymes, which allows expressing the genomic makeup of a given species as a numerical vector. Hierarchical clustering of these vectors functionally groups eukaryote proteomes and reveals convergent evolution, in particular metabolic reduction in obligate endoparasites. We experimentally explore sterol metabolism by testing a set of sterol biosynthesis inhibitors against trypanosomatids, Plasmodium falciparum, Giardia, and mammalian cells, and by quantifying the expression levels of sterol biosynthetic genes during the different life stages of T. cruzi and Trypanosoma brucei. The phenotypic data correlate with genomic makeup for simvastatin, which showed activity against trypanosomatids. Other findings, such as the activity of terbinafine against Giardia, are not in agreement with the genotypic profile.
Faculties and Departments:09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH)
09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH) > Department of Medical Parasitology and Infection Biology (MPI) > Parasite Chemotherapy (Mäser)
UniBasel Contributors:Wenk, Markus and Guan, Xueli and Mäser, Pascal
Item Type:Article, refereed
Article Subtype:Research Article
Bibsysno:Link to catalogue
Publisher:American Society for Biochemistry and Molecular Biology
ISSN:0022-2275
e-ISSN:1539-7262
Note:Publication type according to Uni Basel Research Database: Journal article
Language:English
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Last Modified:21 Nov 2017 13:17
Deposited On:15 Aug 2014 07:16

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